Clinical History
Mar 02: 12 yr old Hispanic female s/p renal transplant (living related donor, 5/6 haplotype
match) following septic shock-induced renal failure, four drug immunosuppression Sept 02:
Acute rejection episode confirmed by renal biopsy, treated with Solumedrol
Dec 02: Develops
febrile illness with monocytosis, lymphadenopathy, serologic studies and cervical node biopsy
obtained.
Case 3 - Figure 1 - Lymph node biopsy, shows effacement of the lymph node architecture by a polymorphic lymphoid proliferation
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Case 3 - Figure 2 - Higher power of lymph node biopsy showing atypical lymphocytes admixed with plasma cells and immunoblasts.
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Case 3 - Figure 3 - CD3 staining - Immunostains showing an admixture of CD3+ T-cells and CD20+ B-cells without kappa or lambda restriction characteristic of polymorphous post-transplant lymphoproliferative disorder.
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Case 3 - Figure 4 - CD20 staining - Immunostains showing an admixture of CD3+ T-cells and CD20+ B-cells without kappa or lambda restriction characteristic of polymorphous post-transplant lymphoproliferative disorder.
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Case 3 - Figure 5 - Kappa light chain staining - Immunostains showing an admixture of CD3+ T-cells and CD20+ B-cells without kappa or lambda restriction characteristic of polymorphous post-transplant lymphoproliferative disorder.
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Case 3 - Figure 6 - Lambda light chain staining - Immunostains showing an admixture of CD3+ T-cells and CD20+ B-cells without kappa or lambda restriction characteristic of polymorphous post-transplant lymphoproliferative disorder.
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Diagnosis
Post-Transplant Lymphoproliferative Disorder
Discussion
PTLD comprises a spectrum of clinicopathologic conditions associated with hyper-proliferation of B
lymphocytes (rarely T lymphocytes or plasma cells) arising in a setting of iatrogenic transplant-related
immunodeficiency. At least 80% of all PTLD cases are Epstein-Barr virus (EBV) associated, i.e. the
majority of proliferating cells are EBV-infected. The median interval to PTLD following transplantation
is 6-10 months. This interval is highly dependent upon degree of immunosuppression, with higher drug
levels associated with more rapid PTLD development. EBV-positive cases occur earlier than EBV-negative
cases. In fact, most PTLD cases that occur more than 5 years after transplant are EBV negative.
Although the overall incidence of PTLD in solid organ transplantation is low (<2%), the incidence
is significantly increased in several situations, including EBV-seronegative children, HLA-mismatched or
T cell depleted bone marrow transplant recipients, and recipients requiring high doses of
immunosuppressive medications, such as patients with graft versus host disease (GVHD), and heart-lung or
liver-bowel transplants.
Syndromes range from a benign infectious mononucleosis-like disorder associated with polyclonal
lymphoid hyperplasia to de novo malignant diffuse large cell lymphoma. There are two forms of so-called
"early" lesions, including the infectious mononucleosis-like form and the plasmacytic
hyperplasia form. In both cases, the lesions are considered to represent benign polyclonal
lymphoproliferative conditions. These lesions are more common in children, and tend to be confined to
lymphoid tissues. In both cases, architectural features of affected lymphoid tissues are at least
partially preserved. IM-like lesions are characterized by paracortical immunoblastic hyperplasia, while
plasmacytic lesions are characterized by a diffuse predominance of plasma cells with reactive features.
If these lesions are EBV negative, they are highly unlikely to represent true PTLD.
Polymorphic PTLD is characterized by architectural effacement, yet is composed of a full
spectrum of lymphoid cells, including B cells, plasma cells, and immunoblasts. Areas of necrosis,
bizarre large cells, and mitotic figures may be seen. In most cases, although morphological polymorphic,
these lesions are monoclonal as demonstrated by immunoglobulin gene rearrangement assay.
Monomorphic PTLD exhibits all the features of de novo diffuse large B cell lymphoma, i.e.
architectural effacement, monomorphic population of large abnormal lymphoid cells, necrosis, and high
mitotic rate. These lesions should be classified as B cell lymphoma of PTLD type. Rare forms of PTLD
include plasma cell myeloma, various subtypes of T cell lymphoma, and Hodgkin's lymphoma. Unlike the
early lesions, both monomorphic and polymorphic PTLD often involve extranodal sites.
Virtually all forms of PTLD, with the exception of plasma cell myeloma and T cell lymphoma, are
strongly linked to EBV infection. EBV infection of human B cells in-vitro induces cell transformation,
i.e. a state of perpetual proliferation, controlled only by a cytotoxic T cell predominant anti-viral
immune response. In a setting of iatrogenic immunosuppression, this T cell response is severely
compromised, this allowing for unregulated EBV-infected B cell (rarely plasma cell or T cell)
proliferation. With multiple rounds of cell proliferation, the possibility of random mutation
increases. If mutations occur in genes associated with cell growth control such as c-myc or p53, the
EBV-infected B cells acquire a malignant phenotype, and malignant lymphoma arises. Very little is known
about EBV-infected T cells.
Detection of EBV in PTLD tissues is probably best accomplished by colorimetric EBER in-situ
hybridization rather than by EBV DNA in-situ hybridization or LMP-1 immunostaining. EBV-infected B cells
in PTLD invariably express 106-107 copies of intranuclear EBER RNA per cell, and
thus EBV detection by EBER in-situ hybridization is highly sensitive. In addition, EBER in-situ
hybridization is highly specific – non-specific staining does not occur. In contrast, non-specific LMP
immunostaining may be seen in EBV-negative plasma cells and plasmacytoid B cells, and some EBV-infected B
cells in PTLD may be negative for LMP-1 expression. EBV DNA in-situ hybridization is a difficult and
impractical method for detection of EBV in tissues. The harsh conditions of prehybridization required
for DNA in-situ hybridization, coupled with the relatively low virus genome copy number in each infected
cell and the problem of non-specific hybridization, conspire to make EBV DNA in-situ hybridization highly
problematic.
Treatment of PTLD is largely dependent upon type of transplant, stage of disease, and pathologic
grade. If the disease is polyclonal, i.e. an "early" lesion, treatment consists of acyclovir and
reduction of iatrogenic immunosuppression. However, the positive benefit of reduction in
immunosuppression should be weighed against the risk of transplant organ rejection, i.e. kidney rejection
may be tolerable while cardiac rejection is intolerable. Although most often monoclonal, polymorphic
PTLD may respond to reduction in immunosuppression. Monomorphic PTLD, on the other hand, is usually
treated as malignant lymphoma with anti-neoplastic chemotherapy. Overall mortality for solid organ
transplant PTLD is 60% and marrow transplant PTLD 80%.
An excellent review of this topic is provided by:
- NL Harris, SH Swerdlow, G Frizzera, and DM Knowles. Post-transplant lymphoproliferative disorders. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds.): World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001.
